Rotaviruses are double stranded RNA viruses of the family Reoviridae. These viruses replicate in the intestinal epithelial cells of a wide range of animal species including most mammalian and avian species and are the major etiological agents of several gastrointestinal disorders in humans and other animals. For example, rotaviruses are responsible for infantile diarrhea and enteritis, causing infant morbidity and mortality. Rotaviruses also cause diarrhea illnesses in calves and piglets, as well as other mammals. These viruses are responsible for debilitating diarrhea in immune-compromised patients such as transplant recipients and AIDS sufferers and have been implicated as a significant cause of traveler's diarrhea. Currently, there is no effective prophylactic or therapeutic drug available to combat rotaviral disorders and attempts to develop vaccines have been problematic.
In order to infect cells and replicate, viruses bind specific receptors on the target cell surface. After attachment, the virus fuses with the cell membrane and is internalized where it uses the target cell's own metabolism to replicate. The initial attachment process is therefore essential to successful infection.
The details of the initial interaction between rotaviruses and the host cell surface have not been completely elucidated. However, sialic acid appears to be an important component of the rotavirus receptor, Yolken et al., J. Clin. Invest. 79: 148-154 (1987), and asialo GM1 binds rotavirus and inhibits viral replication in plaque reduction assays. Willoughby et al., abstract from Proceedings of U.S.-Japan International Rotavirus Meeting, Anapolis, Md. August 1989. Furthermore, bovine submaxillary mucin and chicken ovoinhibitor have been shown to prevent rotavirus gastroenteritis in mice. Yolken et al., supra. Additionally, it has been shown that rotavirus strains isolated from one species cross-react with hosts of another species (see e.g. Leece et al., Infect. Immun. 14: 816-825 (1976); Mebus et al., Infect. Immun. 14: 471-474 (1976); Wyatt et al., Science 207: 189-191 (1980)), suggesting conservation of rotaviral receptors between species.
Molecules able to interact with rotavirus or target cell rotaviral binding proteins could be used as antiviral agents to prevent the subsequent infection of host cells. A distinct advantage of such an approach over traditional methods of preventing viral infections, e.g. vaccines, is that the portion of the viral protein normally binding to the specific cell surface carbohydrate does not mutate. Thus, antiviral agents which act by preventing viral binding are likely to remain effective in the face of mutations to other parts of the viral genome.
Cholesterol 3-sulfate is a lipid constituent of mammalian plasma membrane and has the following structure. ##STR1## This substance is particularly noted in epithelial cells during differentiation. Jetten et al., J. Invest. Dermatol. 92: 203 (1989). Cholesterol 3-sulfate has been postulated to relate to polarity of cell growth in tissue culture. Nichols et al., J. Lipid Res. 29: 1205 (1988).